Is ASPM p.Arg2229fs (c.6686_6689del) pathogenic?

ASPM p.Arg2229fs (c.66866689del) is classified Pathogenic in ASPM (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-13). Very rare (popmax 0.00439%, sas); Associated with microcephaly 5, primary, autosomal recessive.

What condition is associated with ASPM p.Arg2229fs (c.6686_6689del)?

ASPM p.Arg2229fs (c.6686_6689del) is associated with microcephaly 5, primary, autosomal recessive (ClinVar).

How common is ASPM p.Arg2229fs (c.6686_6689del) in the general population?

ASPM p.Arg2229fs (c.6686_6689del) is very rare (popmax 0.00439%, sas) (gnomAD).

ASPM p.Arg2229fs

c.6686_6689del · rs770540184 · VCV694011

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Conditions

microcephaly 5, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 28
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2	GERP -3.1
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,022 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00062% 10/1,611,988 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,756
African / African-American	0.00401%	24,907
European (non-Finnish)	0.000254%	393,006

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ASPM
Protein: p.Arg2229fs
Coding: c.6686_6689del
MANE Select: NM_018136
dbSNP: rs770540184
Type: Microsatellite
Location: chr1:197102562 (GRCh38)
Gene constraint: LOEUF 0.766 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

Full ASPM gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcephaly 5, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ASPM p.Arg1315fs Pathogenic ★★ same condition
ASPM p.Arg1416_Tyr1417insTer Pathogenic ★★ same condition
ASPM p.Arg1576fs Pathogenic/Likely pathogenic ★★ same condition
ASPM p.Asn653fs Pathogenic ★★ same condition
ASPM p.Gln2836fs Pathogenic/Likely pathogenic ★★ same condition
ASPM p.Glu385fs Pathogenic ★★ same condition
ASPM p.Ile2113fs Pathogenic ★★ same condition
ASPM p.Leu1864fs Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/aspm-p-arg2229fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown